Science and Research

Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Results: Peak plasma concentrations (C(max)) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on C(max) values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman's rho test indicated that patient weight and age have an effect on the C(max) of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on C(max) of ivacaftor M6 and on T(max) of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters C(max) and T(max), was observed among the CF patients. Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.
  • Hanafin, P. O.
  • Sermet-Gaudelus, I.
  • Griese, M.
  • Kappler, M.
  • Ellemunter, H.
  • Schwarz, C.
  • Wilson, J.
  • Tan, M.
  • Velkov, T.
  • Rao, G. G.
  • Schneider-Futschik, E. K.

Keywords

  • cystic fibrosis
  • cytochrome interactions
  • drug- drug interactions
  • ivacaftor
  • lumacaftor
  • pharmacodynamics
  • pharmacokinetic
  • JW: Funding of clinical trials and consultancy from Vertex Pharmaceuticals Inc. and
  • Vertex Pharmaceuticals Pty Ltd Australia. MG reports non-financial support from
  • Vertex Corporated, outside the submitted work
  • IS-G. PI of vertex studies and have
  • participated to scientific advisory boards. The remaining authors declare that the
  • research was conducted in the absence of any commercial or financial relationships
  • that could be construed as a potential conflict of interest.
Publication details
DOI: 10.3389/fphar.2021.577263
Journal: Front Pharmacol
Pages: 577263 
Work Type: Original
Location: CPC-M
Disease Area: CFBE
Partner / Member: KUM
Access-Number: 34408649

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